Imidazolyl or imidazoylalkyl substituted with a four or five membered nitrogen containing heterocyclic ring

ABSTRACT

Disclosed is a compound of Formula I: ##STR1## or a pharmaceutically acceptable salt or solvate thereof. Also disclosed are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an effective amount of a Compound of Formula I. 
     Further disclosed is a method of treating allergy (for example asthma), inflammation, hypertension, raised intraocular pressure (such as glaucoma)--i.e., a method of lowering intraocular pressure, sleeping disorders, states of hyper and hypo motility and acidic secretion of the gastrointestinal tract, hypo and hyperactivity of the central nervous system (for example, agitation and depression) and other CNS disorders (such as Alzheimers, Schizophrenia, and migraine) comprising administering an effective amount of a compound of Formula I to a patient in need of such treatment.

The present application is the U.S. national application correspondingto International Application No. PCT/US 92/10743, filed Dec. 17, 1992and designating the United States, which PCT application is in turn acontinuation-in-part of U.S. application Ser. No. 07/809,781, filed Dec.18, 1991 and now abandoned the benefit of which applications are claimedpursuant to the provisions of 35 U.S.C. 120, 363 and 365 (C).

BACKGROUND

H₃ receptor sites are known and are of current interest to those skilledin the art--for example, see: West, Jr. et al., "Biexponential Kineticsof (R)-α-[³ H)Methylhistamine Binding to the Rat Brain H₃ HistamineReceptor", Journal of Neurochemistry, Vol. 55, No. 5, pp. 1612-1616,1990; West, Jr. et al., "identification of Two H₃ -Histamine ReceptorSubtypes", Molecular Pharmacology, 38:610-613; and Korte et al.,"Characterization and Tissue Distribution of H₃ Histamine Receptors inGuinea Pigs by N.sup.α -Methylhistamine", Biochemical and BiophysicalResearch Communications, Vol. 168, No. 3, pp. 9079-986.

Arrang et al. in U.S. Pat. No. 4,767,778 (issued Aug. 30, 1988) disclosea pharmaceutical composition containing a histamine derivative of theformula: ##STR2## wherein each of R₁, R₂, and R₄, represents a hydrogenor a methyl, or R₁ and R₂ taken together represent a methylene, and R₃is a hydrogen, a methyl or a carboxy, with the proviso that R₁, R₂, R₃,and R₄ are not simultaneously methyl groups. It is disclosed that thederivatives behave as complete agonists of the H₃ receptors in rat brainand produce a maximum inhibition of release identical to that induced byhistamine (approximately 60%). It is also disclosed that the histaminederivatives powerfully inhibit the release and synthesis of histamine byvery selectively stimulating the H₃ receptors. Consequently, accordingto Arrang et al., the derivatives are likely to decrease histaminergictransmission in the digestive tract and in the nervous, cardiovascularand immune systems. Arrang et al. disclose that the derivatives can beused in therapy as a drug having sedative effects, as a sleep regulator,anticonvulsant, regulator of hypothalamo-hypophyseal secretion,antidepressant, and modulator of cerebral circulation. According toArrang et al., inhibition of the release of inflammation messengers invarious allergic conditions (e.g., asthma) is expected to result fromstimulation of the H₃ receptors of the lung. It is further disclosedthat the inhibition of release of gastric histamine is likely to exertantisecretory and antiulcerative effects. According to Arrang et al.,modification of release of the messengers of immune responses is likelyto modulate the latter responses.

EP 0 338 939 discloses compounds of the formula: ##STR3##

Derwent abstract 86-273706/42 for EP 0 197 840 discloses imidazolederivatives of the formula: ##STR4## wherein R₁ is H, methyl or ethyl; Ris H or R₂ ; and R₂ is 1-6C alkyl, piperonyl,3-(benzimidazolon-1-yl)propyl, --CZ--NHR₅ or a group (i): ##STR5##wherein n is 0--4; X is a bond, O, S, NH, CO, CH═CH or a group (ii): nn##STR6## R₃ is H, methyl, halo, CN, CF₃ or COR₄ ; R₄ is 1-6C alkyl, 3-6Ccycloalkyl or phenyl (optionally substituted by methyl or F); Z is O, S,NH, N-methyl or N--CN; and R₅ is 1-8C alkyl, 3-6C cycloalkyl (optionallysubstituted by methyl, halo or CF₃), phenyl(1-3C)alkyl, naphthyl,adamantyl or p-toluenesulphonyl. It is disclosed that these compoundsare phychotropic agents. It is also disclosed that these compoundsantagonise the histamine H3 receptors and increase the speed of cerebralhistamine renewal.

Derwent abstract 90-184730/24 for U.S. Pat. No. 4,925,851 discloses 2-or 4-(2-(1H-imidazol-1-yl)ethyl) piperidine compounds useful asantitumour agents for inhibiting lymphoma, sarcoma, myeloma andleukaemia. The compounds have the formula: ##STR7## wherein R is --CH₂(CH₂)_(m) --Me, --CO--(CH₂)_(m) --Me or --CO--CMe₂ --R₂ ; m is 2-18; R₂is H or Me; R₁ is --(CH₂)_(n) --R₃ ; n is 0-13; R₃ is H, i-Pr or t-Bu;and the floating group is at the 2- or 4-position; with the proviso that(1) the sum of C atoms in R₁ does not exceed 13; and (2) the sum of Catoms in R and R₁ does not exceed 25.

Derwent abstract 90-180087/24 for EP 372125A discloses compounds of theformula: ##STR8## wherein X is O or S; R₁ is halo, CF₃, CN, NO₂, OH, or1-6C alkoxy; R₂ is H, 1-6C alkyl, aryl, 7-13C aralkyl, optionallysubstituted amino or 5- or 6-membered N-containing ring; and R₃ is 1-6Chydrocarbyl, 7-13C aralkyl or 1-13C acyl. It is disclosed that thesecompounds have alpha2-antagonist activity with no dopamine activity andthat they are useful for treating depression and other relates illnesses(e.g., anxiety or cognitive disorders).

Derwent abstract 88-309195/55 or U.S. Pat. No. 4,935,417 disclosedcompounds of the formula: ##STR9## wherein (according to U.S. Pat. No.4,935,417) R¹ is aryl, lower alkyl, cycloalkl or hydrogen; R² is aryl,lower alkyl or hydrogen; R³ is lower alkyl, hydroxy or hydrogen; R⁴ isaryl or hydrogen; R⁵ is aryl or hydrogen; m is two or three; n is zero,one or two, provided that when R³ is hydroxy, n is one or two; and q iszero, one, two or three. U.S. Pat. No. 4,935,417 discloses that thesecompounds are calcium channel antagonists useful for treating mammalshaving a variety of disease states, such as stroke, epilepsy,hypertension, angina, migraine, arrhythmia, thrombosis, embolism andalso for treating of spiral injuries.

Compounds known in the art include: ##STR10##

Known compounds in the art also include compounds of the formula:##STR11## wherein R (Table 1) is:

                  TABLE 1                                                         ______________________________________                                        NO.  R                  RN       CA                                           ______________________________________                                        1    --CH.sub.3         106243-  106(11):84602r                                                       44-1                                                  2    --CH(CH.sub.3)2    106243-  106(11):84602r                                                       45-2                                                  3    H                  106243-  106(11):84602r                                                       23-6                                                  4    --C(S)NHC(CH.sub.3).sub.2 CH.sub.2 C(H.sub.3)                                                    106243-  106(11):84602r                                                       93-0                                                  5    --C(O)NHCH(CH.sub.3)(phenyl)                                                                     106243-  --                                                                   90-7                                                  6    --C(S)NH(p-chlorophenyl)                                                                         106243-  --                                                                   85-0                                                  7    --C(O)NH(phenyl)   106243-  --                                                                   77-0                                                  8    --C(NH)N(CH.sub.3)(cyclopropyl)                                                                  106243-  --                                                                   73-6                                                  9    --C(S)NHCH.sub.3   106243-  --                                                                   61-2                                                  10   --CH.sub.2 CH.sub.2 -phenyl                                                                      106243-  --                                                                   49-6                                                  11   --CH.sub.2 CH.sub.2 -p-flurophenyl                                                               106243-  --                                                                   67-8                                                  12   benzyl             106243-  --                                                                   25-8                                                  ______________________________________                                    

Additionally known compounds include: ##STR12##

In view of the art's interest in compounds which effect the H₃receptors, novel compounds having agonist or antagonist activity on H₃receptors would be a welcome contribution to the art. This inventionprovides just such a contribution by providing novel compounds having H₃agonist or antagonist activity.

SUMMARY OF THE INVENTION

This invention provides compounds of the formula: ##STR13## or apharmaceutically acceptable salt or solvate thereof, wherein: (A) m isan integer selected from the group consisting of: 0, 1, and 2;

(B) n and p are integers and are each independently selected from thegroup consisting of: 0, 1, 2, and 3 such that the sum of n and p is 2 or3 such that when the sum of n and p is 2, T is a 4-membered ring andwhen the sum of n and p is 3, T is a 5-membered ring;

(C) each R¹, R², R³, R⁴, R⁶, R⁷, and R⁸ is independently selected fromthe group consisting of:

(1) H;

(2) C₁ to C₆ alkyl;

(3) C₃ to C₆ cycloalkyl; and

(4) --(CH₂)_(q) --R⁹ wherein q is an integer of: 1 to 7, and R⁹ isselected from the group consisting of: phenyl, substituted phenyl,--OR¹⁰, --C(O)OR¹⁰, --C(O)R¹⁰, --OC(O)R¹⁰, --C(O)NR¹⁰ R¹¹, CN and --SR¹⁰wherein R¹⁰ and R¹¹ are as defined below, and wherein the substituentson said substituted phenyl are each independently selected from thegroup consisting of: --OH, --O--(C₁ to C₆)alkyl, halogen, C₁ to C₆alkyl, --CF₃, --CN, and --NO₂, and wherein said substituted phenylcontains from 1 to 3 substituents; examples of --(CH₂)₁ --R⁹ includebenzyl, substituted benzyl and the like, wherein the substituents on thesubstituted benzyl are as defined above for said substituted phenyl;

(D) R⁵ is selected from the group consisting of:

(1) H;

(2) C₁ to C₂₀ alkyl;

(3) C₃ to C₆ cycloalkyl;

(4) --C(O)OR^(10') ; wherein R^(10') is the same as R¹⁰ defined belowexcept that R^(10') is not H;

(5) --C(O)R¹⁰ ;

(6) --C(O)NR¹⁰ R¹¹ ;

(7) allyl;

(8) propargyl; and

(9) --(CH₂)_(q) --R⁹, wherein q and R⁹ are as defined above with theproviso that when q is 1 when R⁹ is not --OH or --SH;

(E) R¹⁰ and R¹¹ are each independently selected from the groupconsisting of: H, C₁ to C₆ alkyl, and C₃ to C₆ cycloalkyl; and, for thesubstituent --C(O)NR¹⁰ R¹¹, R¹⁰ and R¹¹, together with the nitrogen towhich they are bound, can form a ring having 5, 6, or 7 atoms;

(F) the dotted line ( . . . ) represents a double bond that isoptionally present when m is 1, and T is a 5-membered ring, and n is not0, and p is not 0(i.e., the nitrogen in the ring is not bound directlyto the carbon atom bearing the double bond), and when said double bondis present then R² and R⁸ are absent;

(G) when m is 2, each R¹ is the same or different substituent for eachm, and each R² is the same or different substituent for each m;

(H) when n is 2 or 3, each R³ is the same or different substituent foreach n, and each R⁴ is the same or different substituent for each n, and

(I) when p is 2 or 3, each R⁶ is the same or different substituent foreach p, and each R⁷ is the same or different substituent for each p.

This invention also provides pharmaceutical compositions comprising apharmaceutically acceptable carrier and an effective amount of aCompound of Formula I.

This invention further provides a method of treating allergy, (forexample asthma), inflammation, hypertension, raised intraocular pressure(such as glaucoma)--i.e., a method of lowering intraocular pressure,sleeping disorders (e.g., hypersomnia, somnolence, narcolepsy andsleeplessness, such as insomnia), states of hyper and hypo motility andacidic secretion of the gastrointestinal tract, hypo and hyperactivityof the central nervous system (for example, agitation and depression)and other CNS disorders (such as Alzheimers, Schizophrenia, andmigraine) comprising administering an effective amount of a compound ofFormula I to a patient in need of such treatment.

DETAILED DESCRIPTION OF THE INVENTION

As used herein the following terms have the following meanings unlessindicated otherwise:

alkyl--represents a straight or branched, saturated hydrocarbon chainhaving from 1 to 20 carbon atoms;

cycloalkyl--represents a saturated carbocyclic ring having from 3 to 6carbon atoms; and

halogen (halo)--represents fluoro, chloro, bromo or iodo.

Preferably, for compounds of Formula I, m is 0 or 1; R⁵ is selected fromthe group consisting of H and C₁ to C₂₀ alkyl; and R¹ to R⁴ and R⁶ to R⁸are each independently selected from the group consisting of: H, C₁ toC₆ alkyl, and --(CH₂)_(q) --R⁹ wherein R⁹ is phenyl. Most preferably, R⁵is selected from the group consisting of H and methyl; and R¹, R², R³,R⁴, R⁵, R⁶, R⁷, and R⁸ are each independently selected from the groupconsisting of: H, methyl, ethyl, pentyl, benzyl, and 2-phenylethyl.

Representative compounds of this invention include compounds of theformula: ##STR14## wherein m and R¹ to R⁸ are as defined for Formula I.

Representative compounds of Formula II include compounds of FormulasII-1, II-2 and II-3; ##STR15## wherein R¹, R², R³, R⁵, and R⁸ are asdefined for Formula I.

Preferably, for compounds of Formula II, R³, R⁴, R⁶, and R⁸ are H.Preferred compounds of Formula II are represented by compounds ofFormulas IIb and IIC: ##STR16## wherein R¹ and R² are as defined forFormula I with H being preferred, R⁵ is as defined for Formula I with Hand methyl being preferred and R⁷ is selected from the group consistingof H, C₁ to C₆ alkyl, and --(CH₂)_(q) --R⁹ wherein R⁹ is phenyl.Preferably, R⁷ is C₁ to C₆ alkyl, and most preferably methyl.

Representative compounds of Formula IIA include compounds of FormulasIIA-1 and IIA-2: ##STR17## wherein R¹, R², and R⁵ are as defined forFormula I.

Representative compounds of Formula III include compounds of FormulasIII-1 and III-2: ##STR18## wherein R¹, R², and R⁵ are as defined forFormula I.

Representative compounds of Formulas IV include compounds of FormulasIV-1, IV-2, IV-3, IV-4, IV-5, IV-6 and IV-7: ##STR19## wherein R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as defined for Formula I.

Representative compounds of Formula IV also include compounds ofFormulas IV-8, IV-9, and IV-10: ##STR20## wherein R¹, R³, R⁵, and R⁶ areas defined for Formula I.

Representative compounds of Formulas I include: ##STR21##

Certain compounds of the invention may exist in different isomeric(e.g., enantiomer and diastereoisomers) forms. The inventioncontemplates all such isomers both in pure form and in admixture,including racemic mixtures. Enol forms are also included.

The compounds of Formula I can exist in unsolvated as well as solvatedforms, including hydrated forms, e.g., hemi-hydrate. In general, thesolvated forms, with pharmaceutically acceptable solvents such as water,ethanol and the like are equivalent to the unsolvated forms for purposesof the invention.

Certain compounds of the invention will be acidic in nature, e.g. thosecompounds which possess a carboxyl or phenolic hydroxyl group. Thesecompounds may form pharmaceutically acceptable salts. Examples of suchsalts may include sodium, potassium, calcium, aluminium, gold and silversalts. Also contemplated are salts formed with pharmaceuticallyacceptable amines such as ammonia, alkyl amines, hydroxyalkylamines,N-methylglucamine and the like.

Certain basic compounds of the invention also form pharmaceuticallyacceptable salts, e.g., acid addition salts. For example, the nitrogenatoms may form salts with acids. Examples of suitable acids for saltformation are hydrochloric, sulfuric, phosphoric acetic, citric, oxalic,malonic, salicyclic, malic, fumaric, succinic, ascorbic, maleic,methanesulfonic and other mineral and carboxylic acids well known tothose in the art. The salts are prepared by contacting the free baseform with a sufficient amount of the desired acid to produce a salt inthe conventional manner. The free base forms may be regenerated bytreating the salt with a suitable dilute aqueous base solution such asdilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodiumbicarbonate. The free base forms differ from their respective salt formssomewhat in certain physical properties, such as solubility in polarsolvents, but the acid and base salts are otherwise equivalent to theirrespective free base forms for purposes of the invention.

All such acid and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

The following processes may be employed to produce compounds of FormulaI. Unless stated otherwise, reactions are conducted at an appropriatetemperature which allows the reaction to proceed at a reasonable rate tocompletion. Also, unless indicated otherwise, the substituent groupsreferred to in the following processes are as defined above in FormulaI.

A. Preparation of Compounds Wherein m is 0, n is 1 and p is 1 ProducingCompounds of Formula II Step 1--Preparation A ##STR22##

In step 1, commercially available compound (1* is dissolved in asuitable alcohol, ROH wherein R is a lower alkyl such as a C₁ to C₆alkyl (e.g., methyl, ethyl, isopropyl and the like), preferablymethanol, containing a catalytic amount of concentrated hydrochloricacid or similar acid. The reaction mixture is heated at a temperature ofabout 50° to about 70° C. to produce compound (2). There are many otheresterification methods known in the art that may also be employed.

Step 2--Preparation A ##STR23##

In Step 2, compound (2) is reacted with compound (3) in a polar organicsolvent at a temperature of about 0° to about 50° C. in the presence ofan organic base to produce compound (4). In compounds (3) and (4), Zrepresents the protecting group: ##STR24## (trityl group). Z can beother protecting groups, such as 2-(trimethylsilyl)ethoxymethyl,benzyloxycarbonyl, and the like; however, unless stated otherwise, Zpreferably represents the trityl group in the processes described belowfor making the compounds of this invention. Suitable organic solventsinclude: DMF (N,N-dimethylformamide), CH₂ Cl₂ and the like. DMF ispreferred. Preferably, triethylamine is used as the base. Other suitablebases include N,N-diisopropylethylamine and the like.

Those skilled in the art will appreciate that other protecting groupsknown in the art may be used--such as, for example, base sensitivegroups wherein the protected compounds would be deprotected using basicconditions (e.g., NaOH). The processes described herein wherein theprotected compound is deprotected under acidic conditions may also becarried out under basic conditions when a base sensitive protectinggroup is used.

Step 3--Preparation A ##STR25##

In Step 3, the enolate of compound (4) reacts with R⁸ --L in an organicsolvent to produce compound (5). The reaction is conducted at atemperature in the range of about 0° to about 50° C. L is a suitableleaving group such as Cl, Br, I and the like. Preferably, LDA (lithiumdiisopropylamide) is used as the organic base to form the enolate, butother suitable bases include sodium hydride and the like. Suitableorganic solvents include tetrahydrofuran, 1,4-dioxane and the like.Preferably, THF (tetyrahydrofuran) is used

Step 4--Preparation A ##STR26##

In Step 4, the enolate of compound (5) is reacted with compound (6) inan organic solvent in the presence of a Lewis acid to produce compound(7). Suitable organic solvents include tetrahydrofuran, diethyl ether,1,4-dioxane and the like. Preferably, tetrahydrofuran or diethyl etheris used. Suitable organic bases used to generate the anion of (5)include lithium diisopropylamide, LiN(Si(CH₃)₃)₂, and NaH. Preferably,LiN(Si(CH₃)₃)₂ is used. Representative Lewis acids include BF₃ .(C₂ H₅)₂O, (CH₃)₃ SiCl and the like, with BF₃. (C₂ H₅)₂ O being preferred. Thereaction is conducted at a temperature within the range of about -78° toabout 0° C.

Compound (7) is converted to compound (8) by reacting compound (7) withAl(R¹²)₃ in an organic solvent at a temperature of about 50° C. R¹² is asuitable alkyl group such as methyl, ethyl, isopropyl, butyl, and thelike. Methylene chloride is a preferred solvent for this reaction, butothers, such as 1,2-dichloroethane, can be employed.

Compound (6) in Step 4 is prepared according to known in the artprocedures--for example: Cainelli et al., Tetrahedron Letters, Vol. 28,No. 44, p. 5369 (1987); and Uyehara et al., Tetrahedron Letters, Vol.30, No. 32, p. 4275 (1989). In compound (6), R³ is as defined above.

Steps 5, 6 and 7--Preparation A ##STR27##

In Step 5, compound (8) is reduced to compound (9). The reaction isconducted in an organic solvent at a temperature within the range ofabout 20° to about 70° C. using a known reducing agent. Examples ofsuitable reducing agents include DIBALH (diisobutyl aluminium hydride)and AlH₃. Preferably tetrahydrofuran is used as the organic solvent, butother suitable solvents include 1,4-dioxane and the like.

In Step 6, compound (9) is reacted with (i) R⁵ --X (when R⁵ is--C(O)R¹⁰, --C(O)OR^(10'), --C(O)NR¹⁰ R¹¹ or alkyl) in an organicsolvent optionally in the presence of a suitable base (e.g.,triethylamine) or (ii) R^(5A) --CHO (when R⁵ is alkyl, cycloalkyl,allyl, propargyl, benzyl or substituted benzyl) in the presence of NaBH₃(CN) (sodium cyanoborohydride) or other hydrogenating conditions (e.g.H₂ /Rd/ROH) in an organic solvent; to produce compound (10). R^(5A)represents an R⁵ group that has one less --CH₂ -- group. Preferably, CH₂Cl₂ is used as the solvent when R⁵ --X is used, and tetrahydrofuran oran alcohol is used as the solvent when R^(5A) --CHO is used. Xrepresents a suitable leaving group such as Cl, Br, I, or --OCH₃. Thereaction ((i) or (ii)) can be performed at a temperature within therange of about -30 to about 80° C. Compound (10), when R⁵ is --C(O)NR¹⁰H, is prepared by reacting compound (9) with O═C═N--R¹⁰ in an organicsolvent, such as CH₃ CH or toluene. The reaction is performed at atemperature in the range of about 20° to about 110° C. Alternatively,compounds wherein R⁵ is --C(O)NR¹⁰ R¹¹ may be made from compoundswherein R⁵ is --C(O)OR^(10') by reacting such compounds with NHR¹⁰ R¹¹in an organic solvent (e.g., THF) at a temperature of about 25° to about100° C. Compound (9), or compound (10) wherein R⁵ is --C(O)O(t-butyl),can be reacted with aqueous acid (e.g., HCl, HBr, and the like), at atemperature of about 25° to about 100° C., to produce compound (11)wherein R⁵ is H.

In Step 7, compound (10) is deprotected by treatment with dilute aqueousacid, such as HCl or HBr, at a temperature of about 25° to about 90° C.to produce compound (11). Other protecting groups are removed by methodswell known in the art.

In all the preparations that follow, intermediate compounds wherein theimidazole nitrogen is protected by Z and the nitrogen of the cyclic fouror five membered amine is substituted with --C(O)O(t-butyl) orunsubstituted, i.e., hydrogen is bound to the amine nitrogen, such as incompounds (10) or (9), respectively, such intermediate compounds can bereacted with aqueous acid (e.g., HCl, HBr, and the like), at atemperature of about 25° to about 100° C., to produce deprotected finalproducts wherein R⁵ is H, e.g., the compound (11).

B. Preparation of Compounds Wherein m is 0, n is 1 and p is 2 ProducingCompounds of Formula IV Step 1--Preparation B ##STR28##

In Step 1, uracanic acid (12) is heated with catalytic amount ofconcentrated sulfuric acid in a solvent R¹³ OH to produce a compound(13). R¹³ is an alkyl group such as methyl, ethyl, and the like. Thereaction is conducted at a temperature equivalent to the boiling pointof the solvent (R¹³ OH), for example 65° C. for methanol.

Step 2--Preparation B ##STR29##

In Step 2, compound (13) is reacted with trityl chloride (see compound(3) in Preparation A above) to produce compound (14), wherein Zrepresents the tityl group. Other suitable compounds which provideprotecting groups (Z) which can be used instead of trityl chlorideinclude SEM (2-(trimethylsilyl)ethoxymethyl) chloride.

Step 3--Preparation B ##STR30##

In Step 3, compound (14) (from Step 2) is reacted with compound (15) toproduce compound (16). The reaction takes place at a temperature withinthe range of about 20° to about 100° C. in an organic solvent containingan organic base. Suitable organic bases include DBU(1,8diazabicyclo[5.4.0]undec-7-ene), and TMG(1,1,3,3-tetramethylguanidine). Suitable solvents include acetonitrile,tetrahydrofuran, N,N-dimethylformamide and the like.

Step 4--Preparation B ##STR31##

In Step 4, compound (16A) (from Step 3) is hydrogenated to producecompound (17). The hydrogenation takes place in an organic solvent,using Raney-Nickel, at a temperature of about 20° to about 60° C.Preferably ethanol is used as the organic solvent. Under theseconditions cyclization occurs in situ to provide the desired lactam(17). ##STR32##

In Step 5, the anion of compound (17) is reacted with R¹⁴ --L to placethe R¹⁴ on the indicated nitrogen atom in compound (18). R¹⁴ can be asuitable protecting group such as Si(CH₃)₂ C(CH₃)₃ or --C(O)O(t-butyl),or R¹⁴ can be an alkyl, cycloalkyl, benzyl, substituted benzyl, allyl,or propargyl group. L is a leaving group, such as Cl, Br, I or --OSO₂CF₃. The reaction is conducted in an organic solvent such as THF,diethyl ether, 1,4-dioxane or DMSO in the presence of a suitable base,such as lithium diisopropylamide or NaH. The reaction takes place at atemperature within the range of about -78° to about 80° C.

Step 6--Preparation B ##STR33##

In Step 6, the enolate of compound (18) reacts with R⁶ --X and then withR⁷ --X to produce compound (19). X represents a suitable leaving group,such as Cl, Br, I or --OSO₂ CF₃. Each reaction to place each substituentgroup on the ring takes place in an organic solvent using an organicbase. Tetrahydrofuran is the solvent usually used; however, othersuitable solvents include 1,4-dioxane, diethyl ether and the like.Examples of organic bases include lithium diisopropylamide, M⁺N[Si(CH₃)₃ ]₂, KH and the like. M⁺ represents a suitable metal cationsuch as Na, Li, K, and the like. The reaction is usually conducted at atemperature of about -78° to about 80° C.

Steps 7, 8 and 9--Preparation B ##STR34##

In Step 7, compound (19) is reduced to compound (20) with a reducingagent in an organic solvent at a suitable temperature. Preferably,LiAlH₄ (lithium aluminium hydride) is used with tetrahydrofuran at atemperature of about 0° to about 70° C. Other suitable reducing agentsinclude BH₃ (borane) and the like. Other organic solvents which may beused include 1,4-dioxane and the like.

In reaction path 1 (compound (20) to (22)), R¹⁴ is alkyl, cycloalkyl,benzyl, substituted benzyl, allyl, or propargyl. In reaction path 2(compound (20) to (21)), R¹⁴ is --Si(CH₃)₂ C(CH₃)₃ or --C(O)O(t-butyl).

In Step 8, following reaction path 1, compound (20) is deprotected byfollowing the procedure in Step 7 of Preparation A to produce compound(22). Alternatively, following reaction path 2, when R¹⁴ is --Si(CH₃)₂C(CH₃)₃, compound (20) is treated with tetrabutylammonium fluoride intetrahydrofuran at a temperature of about 0° to about 50° C. to producecompound (21), or compound (20), when R¹⁴ is --C(O)O(t-butyl), istreated with dilute aqueous acid (e.g., HCl, HBr and the like).

In Step 9, the procedures in Steps 6 and 7 of Preparation A are followedso that compound (21) may be converted to compound (22).

C. Preparation of Compounds Wherein m is 0, n is 1 and p is 2ProducingCompounds of Formula IV Step 1--Preparation C ##STR35##

In Step 1, compound (23), synthesized according to Degraw et al. J.Med., 1977, 20, 1671, wherein Z id the trityl group, is reacted with R⁸--L in an organic solvent, in the presence of an organic base, at atemperature of about 0° to about 50° C. to produce compound (24). L is asuitable leaving group such as, for example, halogen (halides) selectedfrom the group consisting of: Cl, Br, and I; --OSO₂ --C₆ H₄ --CH₃(wherein C₆ H₄ is phenyl); --OSO₂ --CH₃ ; and the like. Suitable organicbases include lithium diisopropylamide, LiN[Si(CH₃)₃ ]₂, and the like.Preferably, the organic solvent is tetrahydrofuran. Other suitablesolvents which may be used include 1,4-dioxane and the like.

Step 2--Preparation C ##STR36##

In Step 2, the anion of compound (24) is treated with compound (25)(wherein R is alkyl) to produce compound (26). The reaction is conductedat a temperature of about -78° to about 50° C. in an organic solventcontaining an organic base. Suitable organic bases include lithiumdiisopropylamide, LiN(Si(CH₃)₃)₂, ad the like. Preferably, the organicsolvent is tetrahydrofuran. Other suitable solvents which may be usedinclude DMF and the like.

Steps 3 and 4--Preparation C ##STR37##

In Step 3, following the procedure set forth in Step 6 of Preparation B,compound (26) is substituted with substituted groups R⁶ and R⁷ toproduce compound (27). Alternatively, compound (27) is prepared by thereaction of compound (24) with compound (26A) ##STR38## under similarconditions for the reaction of compound (24) with compound (25).

In Step 4, compound (27) is reduced using H₂ and Raney-Nickel. Thereduction takes place in ethanol at a temperature of about 25° (roomtemperature) to about 80° C. Other reducing agents can be used such asNaBH₄ /CoCl₂ wherein the reduction takes place in ethanol at about roomtemperature. Subsequent cyclication in situ provides compound (28).

Steps 5,6 and 7--preparation C ##STR39##

In Step 5, compound (28) is reduced to compound (29) in tetrahydrofuranusing LiAlH₄ and a reaction temperature of about 0° to about 70° C.Another suitable reducing agent is BH₃.

In Step 6, compound (29) is converted to compound (30) according to theprocedure described in Step 6 of Preparation A.

In Step 7, compound (30) is deprotected to produce compound (31) byfollowing the procedure described in Step 7 of Preparation A.

D. Preparation of Compounds Wherein m is 0, n is 1 and p is 2 ProducingCompounds of Formula IV Step 1--Preparation D ##STR40##

In Step 1, compound (32) is reacted with compound (33) to producecompound (34). The reaction is conducted in tetrahydrofuran at atemperature of about 25° to about 70° C. Other usable organic solventsbesides tetrahydrofuran include DMF and the like. Compound (32) isprepared following the literature procedure set forth in J. L. Kelley etal., J. Med. Chem., 20, 721(1977). The Wittig reagent, compound (33) iseither commercially available or may be prepared from the correspondingα-halo ketone and triphenylphosphine using standard reaction conditionsknown in the art.

Step 2--Preparation D ##STR41##

In Step 2, compound (34) is reacted with compound (35) to producecompound (36). The reactor is carried out according to the procedure setforth in Step 3 of Preparation B.

Steps 3, 4 and 5--Preparation D ##STR42##

In Step 3, compound (36) is hydrogenated at a temperature of about 25°to about 70° C. using H₂ and Raney-Nickel. The reaction is conducted inethanol in similar fashion to the reaction described in Step 4 ofPreparation C.

In Step 4, following the procedure in Step 6 of Preparation A, compound(37) is reacted with R⁵ --X or R^(5A) --CHO to produce compound (38).

In Step 5, compound (38) is deprotected at a temperature of about 50° toabout 100° C. using aqueous acid such as 10% aqueous hydrochloric acidto produce compound (39).

E. Preparation of Compounds Wherein m is 1, n is 0 and p is 2 or 3Producing Compounds of Formulas IIa and III Step 1--Preparation E##STR43##

In Step 1, compound (40) is reacted with di-tert-butyl dicarbonate((tBOC)₂ O) in an organic solvent in the presence of an organic base.The reaction is conducted at a temperature of about 0° to about 30° C.Preferably, methylene chloride is used as the organic solvent, but othersuitable organic solvents include DMF and the like. Triethylamine isused as the organic base. Other bases which can be used include3-dimethylaminopyridine and the like. In compounds (40) and (41) rrepresents 1 or 2. The desired starting reactant (40) can be obtainedcommercially. In compound (41), the BOC group is chosen as an activatinggroup or nitrogen which increases the kinetic acidity of the α-protonsuch that a lithio salt would result (for example, Step 2). Otheractivating groups or nitrogen, known in the art that can also beemployed include nitroso, phosphoryl, hindered acyl, and formamidyl.(see Alrichimica Acta, Vol. 8, No. 3, 1985).

Step 2--Preparation E ##STR44##

In Step 2, the anion of compound (41) is reacted with compound (42), toproduce compound (43). The reaction is conducted in an organic solventcontaining an organic base and TMEDA (tetramethylethylenediamine). Thereaction is conducted at a temperature of about -78° to about 25° C.(room temperature). Tetrahydrofuran is preferably used as the solvent,other suitable solvents include diethyl ether and the like. The anion of(41) is prepared by metalation of (41) with sec-butyllithium in THF at-78° C. Compound (42) is obtained by reacting compound (32) with anorganometallic reagent R¹ M, wherein M is Li or MgBr, and then withthionyl chloride (SOCl₂).

Steps 3 to 5--Preparation E ##STR45##

In Step 3, compound (43) is treated with HCl or similar acid in an inertorganic solvent such as ethyl acetate or dioxane, at a temperature ofabout 0° C. to selectively deprotected (43) thus producing compound(44).

In Step 4, compound (44) is reacted with R⁵ --X or R^(5A) --CHO inaccordance with the procedure set forth in Step 6 of Preparation A toproduce compound (44A).

In Step 5, compound (44A) is then deprotected to produce compound (45)by following the procedure set forth in Step 7 of Preparation A.

F. Preparation of Compounds Wherein m is 1, n is 0 and p is 2 or 3Producing Compounds of Formulas IIa and III Step 1--Preparation F##STR46##

In Step 1, compound (41)--see Step 1 of Preparation E--is reacted withcompound (32) in accordance with the procedure set forth in Step 2 ofPreparation E. r is 1 or 2.

Steps 2 and 3--Preparation F ##STR47##

In Step 2, compound (46) is oxidized to produce compound (47). Theoxidation is accomplished by treating compound (46) with an oxidizingagent, such as MnO₂ or PDC (pyridinium dichromate), in an inert organicsolvent, such as tetrahydrofuran or methylene chloride, at a temperatureof about 20° to about 70° C.

In Step 3, compound (47) reacts, under usual Wittig reaction conditions,with compound (48) in an organic solvent at a temperature of about 25°to about 70° C. to produce compound (49). In compound (48), R^(1A)represents an R¹ group which has one less --CH₂ -- group. Preferably,the organic solvent is tetrahydrofuran; however, other suitablesolvents, such as 1,4-dioxane and the like, can be used.

Steps 4 and 5--Preparation F ##STR48##

In Step 4, compound (43) is produced when compound (49) is hydrogenatedin tetrahydrofuran with H₂ using a Pd--C (palladium/carbon) catalyst.Other organic solvents which can be used include ethyl acetate, methanoland the like. Other suitable metal catalysts such as Pt, Pd--Al₂ O₃,Ra--Ni, NiB, and Pd--CaCO₃ can also be employed as the hydrogenationcatalyst.

In Step 5, conversion of compound (43) to compound (44) and then tocompound (45) is accomplished by following the same process described inSteps 3, 4, and 5 of Preparation E.

G. Preparation of Compounds Wherein m is 1, n is 1 and p is 1 or 2Producing Compounds of Formulas II and IV Step 1--Preparation G##STR49##

In Step 1, the anion of compound (50) reacts with compound (32) in anorganic solvent at a temperature of about -78° to about 25° C. toproduce compound (51) wherein p is 1 or 2. Suitable organic solventsinclude tetrahydrofuran and the like. Preferably, the organic base usedto generate the anion of (50) is lithium diisopropylamide or M⁺N[Si(CH₃)₃ ]₂ wherein M⁺ is a metal cation such as Li, Na, or K. Z istrityl. Compound (50) is obtained from the commercially availableunprotected precursor ##STR50## according to known methods--see, forexample, Step 5 of Preparation B.

Steps 2-4--Preparation G ##STR51##

In Step 2, compound (51) is reacted with R¹ --Q, wherein Q is Li orMgBr, in tetrahydrofuran containing CuCN and a Lewis acid, such as BF₃,(CH₃)₃ SiCl and the like, to produce compound (52). The reaction isconducted at a temperature of about -78° to about 20° C. Tetrahydrofuranis the preferred organic solvent; however, other suitable solventsinclude diethyl ether and the like.

In Step (3), compound (52) is reacted with R⁸ --L according to theprocedure set forth in Step 3 of Preparation A. Then the resulting R⁸substituted compound is reduced with either AIH₃ or DIBALH (when p=1);or with LiAlH₄ (when p=2) at a temperature of about 25° to about 65° C.to produce compound (53). The reduction is conducted in tetrahydrofuran;however, other organic solvents, such as 1,4-dioxane and the like, canbe used.

In Step 4, compound (53) is converted to compound (54) according to theprocesses described in Steps 8 and 9 of Preparation B for the conversionof compound (20) to compound (22).

H. Preparation of Compounds Wherein m is 1, n is 1 and p is 1 or 2Producing Compounds of Formulas II and IV

The anion of compound (50), which is prepared by reacting compound (50)with lithium diisopropylamide at a temperature of about -20° C. to about20° C. in THF (see Step 1 of Preparation G) reacts with compound(42)--see Step 2 or Preparation E--in tetrahydorfuran at a temperatureof about -78° to about 25° C. to produce compound (52)--see Step 2Preparation G. Other suitable solvents besides tetrahydrofuran can alsobe used, such as DMF and the like. Other suitable bases which can beused to generate the anion of (50) include NaN[Si(CH₃)₃ ]₂, KN[Si(CH₃)₃]₂, KH and the like. Compound (52) is converted to compound (54)following the procedures in Steps 3 and 4 of Preparation G.

I. Preparation of Compounds Wherein m is 1, n is 1 and p is 2 ##STR52##

Compound (55) reacts with R⁵ --M (wherein M is Li, ZnBr or MgBr) intetrahydrofuran containing BF₃. (C₂ H₅)₂ O and CuCN at a temperature ofabout -78° to about 20° C. to produce compound (56). Other suitablesolvents such as diethyl ether can be used. Compound (56) is convertedto compound (57) in accordance with the reaction steps set forth inPreparation G or Preparation H.

Compound (55) is obtained by reacting the commercially availableunprotected precursor ##STR53## with R¹⁴ --L according to knownmethods--see, for example, Step 5 of Preparation B.

J. Preparation of Compounds Wherein m is 2, n is 0 and p is 2 or 3; or mis 2, n is 1 and p is 1 or 2

By following the steps in Preparation E. F, G, or H with the receptionthat compound (58) ##STR54## is used instead of compound (42) andcompound (59) ##STR55## is used in place of compound (32), compounds(60) and/or (61) ##STR56## are produced. Compound (60) is producedfollowing Preparation E or Preparation F, and compound (61) is producedfollowing Preparation G or Preparation H. In compound (60), r is 1 or 2and therefore p is 2 or 3, and in compound (61), p is 1 or 2. Incompound (58), G represents a suitable leaving group such as Br, I,--OSO₂ --C₆ H₄ --CH₃, --OSO₂ --CH₃, --OSO₂ --CF₃ and the like. Thepreparation of compound (58) is described below.

K. Preparation of Compound (58) ##STR57## Compound (62) is produced bythe reduction of compound (23) in tetrahydrofuran at a temperature ofabout 0° to about 70° C. using diisobutylaluminium hydride as thereducing agent followed by an aqueous work up. Alternatively, reductionof compound (4) by bis(2-methoxyethoxy)aluminium hydride also canproduce compound (62), see for example R. Kanazawa & T. Tokoroyama,Synthesis, 526(1976). Compound (59) is produced by reacting compound(62) in an organic solvent containing an organic base with R¹ --L andthen with R² --L in accordance with the method set forth in Step 3 ofPreparation A. Preferably, the organic solvent is tetrahydorfuran andthe organic base is lithium diisopropylamide. L is a suitable leavinggroup such as Cl, Br, I, --OSO₂ --CF₃ and the like.

Alternatively, the sequence of the preparation of compound (59), fromcompound (4) or (23), can be switched, i.e., alkylation first tointroduce R¹ and R² and then reduction. ##STR58## Compound (59) thenreacts with either lithium aluminum hydride (when R¹ ═H) or R¹ --Q (R¹is not H) in tetrahydrofuran at a temperature of about -78° to about 0°C. to produce compound (63). Q represents Li or MgBr. When G representsa halide (i.e., Cl, Br, or I), then compound (58) is produced by eitherreacting compound (63) with (H₅ C₆)₃ P/CG₄ or (H₅ C₆)₃ PG₂ (see Fiser &Fiser, Reagents for Organic Synthesis, Vol. 1, p1247(1967)). When Grepresents --OSO₂ --C₆ H₄ --CH₃, --OSO₂ --CH₃ or --OSO₂ --CF₃, thencompound (58) is produced by reacting compound (63) with Cl--SO₂ --C₆ H₄--CH₃, Cl--SO₂ --CH₃ or Cl--SO₂ --CF₃, respectively, in methylenechloride containing triethylamine (as base) at a temperature of about-78° to about 0° C.

L. Preparation of Compounds Wherein m is 1, n is 1 and p is 2 andWherein the Double Bond Indicated in Formula I is Present ##STR59##

In Step 1, compound (65) is produced when compound (64) is reacted with(t--BOC)₂ O and triethylamine. The reaction is conducted in an organicsolvent, such as methylene chloride or DMF, using a temperature withinthe range of about 0° to about 25° C. (room temperature).

In Step 2, compound (66) is produced by treating compound (65) with anoxidizing agent such as pyridinium dichromate. The oxidation reaction isconducted in an organic solvent, such as methylene chloride, using atemperature of about 25° to about 50° C.

In Step 3, compound (67) is produced when the enolate of compound (66)is reacted with R³ --L wherein L is a suitable leaving group, such ashalogen (e.g., Cl, Br, or I), --OSO₂ CF₃ and the like. The reactiontakes place in an organic solvent, such as tetrahydrofuran or benzene,containing a suitable base, such as NaH, LDA, or LiN(Si(CH₃)₃)₂.Preferably, tetrahydrofuran is used as the solvent and LDA is used asthe base. The reaction is conducted at a temperature of about 0° toabout 80° C.

In Step 4, compound (67) is reacted with R⁴ --L using the same procedureset forth in Step 3 in order to produce compound (68).

In Step 5, compound (69) is produced when compound (68) is first reactedwith R⁶ --L and then reacted with R⁷ --L. Each reaction is conductedusing the same procedure set forth in Step 3.

In Step 6, compound (71) is obtained when compound (69) is reacted withcompound (70) ##STR60## The reaction takes place in an organic solvent,such as tetrahydrofuran, DMF or benzene, containing a suitable base,such as NaH, LDA, or LiN(Si(CH₃)₃)₂. Preferably, tetrahydrofuran is usedas the solvent and LDA is used as the base. The reaction is conducted ata temperature of about 0° to about 80° C. Compound (70) is obtained byreacting ##STR61## with P(C₆ H₅)₃ in an organic solvent, such asmethylene chloride, CH₃ CN, tetrahydrofuran and the like, using atemperature of about 25° to about 50° C. In compounds (70) and (70A), Zrepresents trityl or SEM.

In Step 7, compound (72) is produced by using compound (71) andfollowing the same procedures set forth in Steps 3, 4 and 5 ofPreparation E.

In the steps of Preparation L, alkylations (i.e., Steps 3, 4 and 5) areonly if desired and R³, R⁴, R⁵, R⁶, and R⁷ are as defined for Formula I.

In the above processes, certain functional groups may be incompatablewith some transformations described herein and consequently it issometimes desirable and/or necessary to protect certain groups duringthe reactions. Certain protecting groups are employed in the aboveprocesses but, as those skilled in the art will recognize, otherprotecting groups may be used in their place. Conventional protectinggroups are operable as described in Greene, T. W., and Wuts, P. G. M.,"Protective Groups in Organic Synthesis," John Wiley & Sons, New York,1991; the disclosure of which is incorporated herein by referencethereto. After the reaction or reactions, the protecting groups may beremoved by standard procedures.

The compounds of this invention are either agonists or antagonists ofthe histamine H₃ receptor. The binding affinity of the compounds of theinvention to the H₃ receptor may be demonstrated by the proceduredescribed below:

H₃ Receptor Binding Assay

The source of the H₃ receptors in this experiment was guinea pig brain.The animals used weighted 400-600 g. The tissue was homogenized using aPolytron in a solution of 50 mM Tris, pH 7.5. The final concentration oftissue in the homogenization buffer was 10% w/v. The homogeneates werecentrifuged at 1000×g for 10 min. in order to remove clumps of tissueand debris. The resulting supernatants were then centrifuged at 50,000×gfor 20 min. in order to sediment the membranes, which were next washed 3times in homogenization buffer (50,000×g for 20 min. each). Themembranes were frozen and stored at -70° C. until needed.

All compounds to be tested were dissolved in DMSO and then diluted intothe binding buffer (50 mM Tris, pH 7.5) such that the finalconcentration was 2 μg/mL with 0.1% DMSO. Membranes were then added (400μg of protein) to the reaction tubes. The reaction was started by theaddition of 3 nM [³ H]R-α-methylhistamine (8.8 CVmmol) or [³H]-N-methylhistamine (80 Cvmmol) and incubated at 30° for 30 min. Boundligand was separated from unbound ligand by filtration, and the amountof radioactive ligand bound to the membranes were performed in duplicateand the standard error was less than 10% in all instances. Compoundsthat inhibited greater than 70% of the specific binding of radioactiveligand to the receptor were serially diluted to determine a K_(i) (μM).The results are given in Table 2.

In Table 2, the compound represented by (a*) is known in the art.

                                      TABLE 2                                     __________________________________________________________________________                    H.sub.3             H.sub.3                                                   Binding             Binding                                   COMPOUND        K.sub.i (μM)                                                                    COMPOUND       K.sub.i (μM)                           __________________________________________________________________________     ##STR62##      0.014                                                                               ##STR63##     0.007                                      ##STR64##      0.003                                                                               ##STR65##     0.006                                      ##STR66##      0.17                                                                                ##STR67##     0.008                                      ##STR68##      0.076                                                                               ##STR69##     0.066                                      ##STR70##      0.60                                                                                ##STR71##     0.11                                       ##STR72##      0.003                                                                               ##STR73##     0.15                                       ##STR74##      0.077                                                                               ##STR75##     0.45                                       ##STR76##      7%**                                                                                ##STR77##     68%**                                     __________________________________________________________________________

In Table 2, the "**" values for compounds (o) and (p) represent the %inhibition at a concentration of 2 μg/mL. It is expected that a higherconcentrations higher activities will be obtained.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 70 percentactive ingredient. Suitable solid carriers are known in the art, e.g.magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets,powders, cachets and capsules can be used as solid dosage forms suitablefor oral administration.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides of cocoa butter is first melted, and the activeingredient is dispersed homogeneously therein as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool and thereby solidify.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection.

Liquid form preparations may also include solutions for intranasaladministration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component, e.g., an effectiveamount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 0.1 mg to 1000 mg, more preferably fromabout 1 mg to 500 mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage for a particular situation is withinthe skill of the art. Generally, treatment is initiated with smallerdosages which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under the circumstances is reached. For convenience, thetotal daily dosage may be divided and administered in portions duringthe day if desired.

The amount and frequency of administration of the compounds of theinvention and the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddosage regimen is oral administration of from 1 mg to 2000 mg/daypreferably 10 to 1000 mg/day, in one to four divided doses to achieverelief of the symptoms. The compounds are non-toxic when administeredwithin this dosage range.

The invention disclosed herein is exemplified by the followingpreparative examples, which should not be construed to limit the scopeof the disclosure. Alternative mechanistic pathways and analogousstructures within the scope of the invention may be apparent to thoseskilled in the art.

EXAMPLE 1 A. Preparation of Methyl Ester (2) ##STR78##

To a suspension of urocanic acid 1 (13.8 g, 100 mmol) in methanol (250mL) was added concentrated sulfuric acid (10 mL) and the mixture washeated to reflux for 24 h. The mixture was cooled to 5° C. andconcentrated ammonium hydroxide (25 mL) was added slowly. The solventswere removed by rotary evaporation and to the residue was added water(50 mL) and ethyl acetate (750 mL). The mixture was shaken, the layersseparated, and the aqueous layer was extracted with ethyl acetate (500mL). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and evaporated to give 2 as a white solid (14.9 g,98%).

B. Preparation of (2-Trimethylsily)ethoxymethyl-imidazole (3) ##STR79##

To a suspension of the methyl ester 2 (12.2 g, 80.0 mmol) intetrahydrofuran (80 mL) was added triethylamine (28 mL, 200 mmol) andthen (2-trimethylsilyl)ethoxymethyl chloride (30 mL, 170 mmol). Themixture was stirred at room temperature for 1 h and then to this mixturewas added 5% aqueous sodium hydroxide (200 mL) and methylene chloride(1200 mL). The mixture was shaken vigorously, the layers separated, andthe aqueous layer was extracted with methylene chloride (1200 mL). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered, and evaporated to give an orange, oily residue which waspurified by flash chromatography (ethyl acetate) to give 3 as a slightlyyellow solid (10.8 g, 48%).

C. Preparation of Nitro-Ester (4) ##STR80##

To a solution of unsaturated ester 3 (10.8 g, 38 mmol) in acetonitrile(25 mL) was added nitroethane (15 mL, 209 mmol) and then1,8-diazabicyclo[5.4.0]undec-7-ene (6 mL, 40 mmol). The mixture wasstirred at room temperature for 72 h, the solvents were removed byrotary evaporation and the dark, oily residue was purified by flashchromatography (ethyl acetate) to give the nitro-ester 4 as a mixture ofdiastereomers (13.3 g, 97%).

D. Preparation of Lactams (5t) and (5c) ##STR81##

A mixture of the nitro-ester 4 (8.3 g, 23 mmol) and Raney nickel (8 g)in absolute ethanol (60 mL) was shaken under 60 psi of hydrogen at 55°C. in a Parr apparatus for 6 h. The mixture was filtered and thefiltrate was evaporated to give an oily residue which was purified byflash chromatography (a: 5% MeOH/NH₃ in CH₂ Cl₂, b: 7% MeOH/NH₃ inTHF:Hexane, 2:1) to give two compounds; the first compound to elute wasthe trans-diastereomer 5t (2.64 g, 39%). The second compound to elutewas the cis-diastereomer 5c (1.67 g, 26%).

E. Preparation of pyrrolidine (6t) ##STR82##

To a solution of the trans-lactam 5t (2.60 g, 8.8 mmol) intetrahydrofuran (175 mL) was added a solution of lithium aluminumhydride in diethyl ether (1.0M, 44.0 mL, 44 mmol). The mixture wasstirred at room temperature for 4 h and to the reaction mixture wasadded diethyl ether (440 mL) and saturated aqueous sodium sulfate (7 mL)dropwise. The mixture was dried over anhydrous sodium sulfate, filtered,and evaporated to give an oily residue which was purified by flashchromatography (gradient elution; CH₂ Cl₂ : MeOH/NH₃, 7:1 to 5:1) togive 6t as a colorless oil (1.15 g, 46%).

F. Preparation of pyrrolidine (6c) ##STR83##

The cis-lactam 5c (0.60 g, 2.0 mmol) was treated in the same manner asdescribed for the preparation of pyrrolidine 6t. The crude reactionproduct was purified by flash chromatography (gradient elution; CH₂ Cl₂: MeOH/NH₃, 6:1 to 4:1) to give 6c as a colorless oil (0.36 g, 63%).

G. Preparation of ((±)-7t) ##STR84##

To a solution of the pyrrolidine 6t (563 mg, 2.0 mmol) in 95% ethanol (3mL) was added concentrated hydrochloric acid (1mL) and the mixture washeated to reflux for 16 H. The solvents were removed by rotaryevaporation and to the residue was added 1N aqueous hydrochloric acid (8mL). This solution was extracted with ethyl acetate (3×4 mL) and theaqueous layer was concentrated by rotary evaporation. To the residue wasadded distilled water (15 mL) and the resulting solution was filteredthrough a glass wool plug. The filtrate was concentrated by rotaryevaporation to give (±)-7t as a cream-colored solid (395 mg, 88%).

H. Purification of ((±)-7t) ##STR85##

To a solution of (±)-7t (336 mg, 1.5 mmol) in dimethylformamide (5.0 mL)was added triethylamine (1.05 mL, 7.53 mmol) and then a solution ofdi-tert-butyl dicarbonate (t-BOC)₂ O (720 mg, 3.3 mmol) indimethylformamide (1 mL). The mixture was stirred at room temperaturefor 2 h, the solvents were removed by vacuum distillation (2.0 mm Hg)and the resulting residue was purified by flash chromatography (gradientelution; EtOAc: hexane, 1:1 to 2:1) to give the corresponding di-t-BOCderivative (±)-7't (488 mg) as a white solid. This material wasdissolved in ethyl acetate (3 mL), cooled to 5° C., and to this solutionwas added a saturation solution of hydrogen chloride in ethyl acetate(14 mL). The mixture was gradually warmed to room temperature (30 min)and stirred at this temperature for 16 h. The ethyl acetate was removedfrom the precipitated product by pipet and the precipitate was driedunder high vacuum (0.1 mm Hg) to give (±)-7t as a white solid (286 mg,85% recovery); MS(CI) 152 (M+1).

I. Resolution of ((±)-7t

The racemic (±)-7't was resolved by High Performance LiquidChromatography using a Daicel Chiralcel OJ chiral chromatography column(2.0 cm×50.0 cm, 4% isopropanol in hexane). Multiple injections (13injections of about 150 mg each) provided the levorotatory enantiomer(-)-7't:

    950 mg; [α].sub.D.sup.26 =-12.8°, c=0.50, CHCl.sub.3, and

the dextrorotatory enantiomer (+)-7't:

    904 mg; [α].sub.D.sup.26 =+12.0°, c=0.50, CHCl.sub.3.

Treatment of (-)-7't with a saturation solution of hydrogen chloride inethyl acetate as described above for the purification of (±)-7t provided(-)-7t:

    [α].sub.D.sup.26 =-34.6°, c=1.00, H.sub.2 O.

Similar treatment of (+)-7't gave (+)-7t:

    [α].sub.D.sup.26 =+39.4°, c=1.00, H.sub.2 O.

J. Preparation of ((±)-7c) ##STR86##

The cis-pyrrolidine 6c (394 mg, 1.4 mmol) was treated as described forthe preparation of (±)-7t to give (±)-7c as a cream-colored solid (288mg, 95%). Compound (±)-7c (224 mg, 1.0 mmol) was purified as describedfor the purification of (±)-7t to give (±)-7c as a white solid (177 mg,79% recovery); MS (CI) 152 (M+1).

Compounds 8, 9, 10t, 10c, 11t, 11c, 12t and 12c were prepared using theprocedure described above for (±)-7t and 7c. The procedure is summarizedbelow, A and B, and hence the compounds produced, are defined in Table3.

K. Resolution of (±)-(7c)

In a manner similar to that described in Example 1, Steps H and I,racemic (±)-7c was resolved by High Performance Liquid Chromatographyusing a Daicel Chiralcel OD chiral chromatography column (5.0 cm×50.0cm, 1% isopropaneol in hexane) followed by deprotection with a saturatedsolution of hydrogen chloride in ethyl acetate to give the levorotatoryenantiomer (-)-7c:

    [α].sub.D.sup.26 =-35.7°, c=1.00, H.sub.2 O

and the dextrorotatory enantiomer (+)-7c:

    [α].sub.D.sup.26 =+33.2°, c=1.00, H.sub.2 O. ##STR87##

                  TABLE 3                                                         ______________________________________                                        COM-                               MS(CI)                                     POUND   A            B             (M + 1)                                    ______________________________________                                        8       H            H             138                                        9       --CH.sub.3   --CH.sub.3    166                                        10t     H            --CH.sub.2 CH.sub.3                                                                         166                                        10c     --CH.sub.2 CH.sub.3                                                                        H             166                                        11t     H            --CH.sub.2 C.sub.6 H.sub.5                                                                  228                                        11c     --CH.sub.2 C.sub.6 H.sub.5                                                                 H             228                                        12t     H            --CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                                                         242                                        12c     --CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                                                        H             242                                        ______________________________________                                    

EXAMPLE 2 ##STR88##

To a cooled (0° C.) solution of diisopropylamine (4 mmol, 561 μL) in dryTHF (7 mL) was added n-BuLi (n-butyllithium) (2.5 mL of a 1.6M solutionin hexane) dropwise. After 10 minutes at this temperature, the solutionof LDA was cooled to -30° C. and a solution of 1 trityl-4-cyanomethylimidazole 13 (4 mmol, 1.4 g, Tr=trityl)) in THF (6 mL) was addeddropwise. After an additional 30 minutes at this temperature, a solutionof ethyl-2-bromopropionate (4 mmol; 520 μL) in THF (5 mL) was addeddropwise. The reaction was slowly warmed to RT (room temperature) (45minutes) and quenched with 15 mL H₂ O. The reaction was extracted withdiethyl ether (3×25 mL) and the combined organic fractions were washedwith brine, dried with MgSO₄, and filtered. Concentration of the rotovapyielded 1.65 g of an oil which was purified via column chromatography(75:25 hexane:ethyl acetate). 0.75 g (42%) of 14 was obtained as amixture of diastereomers. MS (CI) 450 (M+1). ##STR89##

To a solution of 14 (6.23 mmol; 2.8 g) and CoCl₂.6 H₂ O (6.23 mmol; 1.48g) in absolute ethanol (150 mL) was added NaBH₄ (31.2 mmol; 1.18 g)portionwise over 30 minutes. After 4 hours, the black reaction mixturewas concentrated to 1/3 the volume, shaken with ice-cold 3N HCl (50 mL)to dissolve the solids and rapidly basified to pH=9 was concentrated NH₄OH. The crude reaction was extracted with ethyl acetate (3×150 mL), thethe combined organic layers were washed with brine, and dried (MgSO₄).Purification on a flash column (250 g SiO₂ ; 93:7 CH₂ Cl₂ : MeOH/NH₃)yielded 1.53 g (60%) of 15 as a white solid. ##STR90##

To a solution of lactam 15 (2.46 mmol; 1 g) in THF (30 mL) was addedlithium aluminum hydride in diethyl ether (1M; 12.2 mL). The reactionwas heated to 50° C. for 5.5 h, cooled to room temperature, diluted withdiethyl ether, and quenched by careful dropwise addition of saturatedaqueous Na₂ SO₄. When H₂ evolution ceased, an additional 50 mL diethylether and solid Na₂ SO₄ was added. The organic layer was filtered andconcentrated to obtain 870 mg of a solid.

To a solution of the solid from the previous step in THF (20 mL) wasadded triethylamine (4.4 mmol; 614 μL) followed by di-t-butyldicarbonate (2.75 mmol; 600 mg). After 2.5 h, brine was added and thereaction was extracted into EtOAc (100 mL). The combined organic layerswere dried (Na₂ SO₄), filtered, and concentrated. 600 mg (48%) of 16 and660 mg (52%) of 17 were obtained after chromatography on a flash column(150 g SiO₂ ; 65:35 EtOAc:Hexane). ##STR91##

A suspension of 16 (1.2 mmol; 600 mg) in 1NHCl (30 mL) was heated to 80°C. for 1 hour. Compound 16 slowly dissolved and was replaced by a newsolid. The reaction was cooled, filtered, and the aqueous layer wasconcentrated. Compound (±)-18, 170 mg, was obtained as a clear glass(64%) MS (EI) 151 (M⁺).

In a similar manner, 17 yielded (±)-19 (175 mg, 60%) MS (EI) 151 (M⁺).##STR92##

E. Resolution of (±)18 and (±)19

In a manner similar to that described in Example 1, Steps H and I,racemic (±)18 and (±)19 were resolved by High Performance LiquidChromatography on a Chiralcel OD preparative column (2×50 cm) and gaveafter deprotection:

    (+)-18 [α].sub.D.sup.21.5 =+37.6°, c=0.43, MeOH

    (-)-18 [α].sub.D.sup.22 =-32.2°, c=0.43, MeOH

    (+)-19 [α].sub.D.sup.22 =+39.0°, c=0.18, MeOH

and

    (-)-19 [α].sub.D.sup.22 =-36.0°, c=0.20, MeOH.

By using the route described above for repairing (±)-18, the compoundslisted in Table 4 were prepared:

                                      TABLE 4                                     __________________________________________________________________________    STARTING                                                                      MATERIAL             PRODUCT          MS                                      __________________________________________________________________________     ##STR93##                                                                                          ##STR94##                                                                                      ##STR95##                               ##STR96##                                                                                          ##STR97##                                                                                      ##STR98##                               ##STR99##                                                                                          ##STR100##                                                                                     ##STR101##                              ##STR102##                                                                                         ##STR103##                                                                                     ##STR104##                             __________________________________________________________________________

EXAMPLE 3 ##STR105##

To a solution of 15 (1.4 mmol; 570 mg; see Step B of Example 2) in DMSO(10 mL) at room temperature was added NaH (1.4 mmol; 56 mg of a 60%dispersion in mineral oil). After 1.5 hours, CH₃ I (1.4 mmol 87 μL) wasadded, and the reaction was stirred overnight. The reaction was dilutedwith H₂ O and extracted into diethyl ether (3×25 mL). The combinedorganic extracts were washed with brine, dried (Na₂ SO₄), filtered, andconcentrated. The crude product was purified on a flash column (100 gSiO₂ ; 95:5 CH₂ Cl₂ : CH₃ OH/NH₃). Compound 22, 290 mg (49%), wasobtained. ##STR106##

By using the route described in Example 2, Steps C and D, compound 22was converted to 23 (62 mg, 67%); MS(CI) 166(M+1).

EXAMPLE 4 A. Preparation of α-methyl-nitrile (24) ##STR107##

To a solution of diisopropylamine (0.775 mL, 5.5 mmol) intetrahydrofuran (15 mL) at -78° C. was added a solution ofn-butyllithium in hexane (2.5 M, 2.1 mL, 5.25 mmol) and the mixture wasstirred at -78° C. for 1 h. To this was added a solution of the nitrile13 (1.75 g, 5.0 mmol, see Step A of Example 2) in tetrahydrofuran (10mL) and the mixture was stirred at -78° C. for 1 h. To this solution wasadded a solution of methyl iodide (325 μL, 5.2 mmol) in tetrahydrofuran(2.5 mL), the mixture was stirred at -78° C. for 30 min and then warmedto 0° C. (1 h). To the mixture was added saturated aqueous ammoniumchloride (2 mL), the solvents were removed by rotary evaporation and tothe residue was added methylene chloride (200 mL), water (25 mL) andsaturated aqueous sodium bicarbonate (25 mL). The mixture was shakenvigorously, the layers separated and the organic layer was dried overanhydrous sodium sulfate, filtered and evaporated to give a yellow solidresidue. This crude product was purified by flash chromatography(hexane:isopropanol, 4:1) to give the α-methyl-nitrile 24 as anoff-white solid (1.33 g, 73%).

B. Preparation of nitrile-ester (25) ##STR108##

To a solution of diisopropylamine (0.550 mL, 3.9 mmol) intetrahydrofuran (12 mL) at -78° C. was added a solution of n-butylithiumin hexane (2.5 M, 1.50 mL, 3.75 mmol) and the mixture was stirred at-78° C. for 1 h. To this was added a solution of the α-methyl-nitrile 24(1.27 g, 3.5 mmol) in tetrahydrofuran (10 mL) and the mixture wasstirred at -78° C. for 1 h. To this solution was added a solution ofethyl bromoacetate (420 μL, 3.79 mmol) in tetrahydrofuran (2.0 mL), themixture was stirred at -78° C. for 1 h and then warmed to 0° C. (1 h).To the mixture was added saturated aqueous ammonium chloride (1.5 mL),the solvents were removed by rotary evaporation and to the residue wasadded methylene chloride (200 mL) and saturated aqueous sodium chloride(40 mL). The mixture was shaken vigorously, the layers separated and theorganic layer was dried over anhydrous sodium sulfate, filtered andevaporated to give a yellow oily residue. This crude product waspurified by flash chromatography (hexane:acetone, 3:1 to 2:1) to givethe nitrile-ester 25 as a colorless glass (1.44 g, 90%).

C. Preparation of Lactam (26) ##STR109##

To a solution of the nitrile-ester 25 (1.39 g, 3.1 mmol) in absoluteethanol (70 mL) was added a solution of cobalt dichloride hexahydrate(736 mg, 3.1 mmol) in absolute ethanol (10 mL) and then portionwise (5min) sodium borohydride (700 mg, 18.5 mmol). The mixture was stirred atroom temperature for 2 h, the solvents were removed by rotaryevaporation and to the black residue was added color (5° C.) 3M aqueoushydrochloric acid (34 mL). The mixture was shaken until the blackprecipitate dissolved (5 min) and then to this mixture was addedconcentrated ammonium hydroxide (10 mL). This solution was extractedwith ethyl acetate (2×250 mL) and the combined organic layers were driedover anhydrous sodium sulfate, filtered and evaporated to give anoff-white solid residue which was purified by flash chromatography(gradient elution: 8% to 10% CH₃ OH/NH₃ in CH₂ Cl₂) to give the lactam26 as a white solid (1.05 g, 83%).

D. Preparation of the Pyrrolidine (27) ##STR110##

The lactam 26 (1.05 g, 2.58 mmol) was treated with a solution of lithiumaluminum hydride in diethyl ether (1.0 M, 13.0 mL, 13.0 mmol) asdescribed for the preparation of the pyrrolidine 6t (see Example 1, StepE). The crude product was purified by flash chromatography (gradientelution: CH₂ CL₂ : CH₃ OH/NH₃, 8:1 to 7:1 to 6:1) to give thepyrrolidine 27 as a colorless glass (720 mg, 71%).

E. Preparation of Compound (28) ##STR111##

A suspension of the pyrrolidine 27 (750 mg, 1.91 mmol) in 1N aqueoushydrochloric acid (15 mL) was heated to reflux for 1 h. The whiteprecipitate that formed during the course of the reaction was removed byfiltration and the aqueous filtrate was extracted with ethyl acetate(2×5 mL). The aqueous layer was concentrated by rotary evaporation togive compound 28 as an off-white solid (390 mg, 91%).

F. Purification of Compound (28)

Compound 28 (75 mg, 0.33 mmol) was purified as described for thepurification of Compound (±)-7t (see Example 1, Step H) to give Compound28 as a white solid (57 mg, 76% recovery); MS (CI) 152(M+1). ##STR112##

EXAMPLE 5

To a solution of 1.08 mL of freshly distilled N,N-diisopropylamine in 1mL of anhydrous THF was added 3.1 mL of 2.5 M n-butylithium at 0° C.under nitrogen. The resulting solution was stirred at 0° C. for 40minutes (resulting in the production of lithium diisopropylamide(LiN(i-Pr)₂)), cooled to -23° C. and then 0.672 mL ofN-methyl-2-pyrrolidinone 29 was added slowly. The solution was stirredfor 0.5 hours at -23° C. and an additional 1 hour at -78° C. A solutionof 2.69 g of 4-chloromethyl-(N-trityl)imidazole 30 in 14 mL of anhydrousTHF was then added dropwise. The resulting solution was stirred for 4hours at -78° C. and slowly warmed to room temperature. After a coupleof hours at -78° C. and slowly warmed to room temperature. After acouple of hours of stirring at room temperature, the reaction mixturewas quenched by water and extracted with ethyl acetate. The combinedorganic extracts were washed with brine, dried over anhydrous MgSO₄ andconcentrated to give crude product. The crude product was purified byflash chromatography on SiO₂ (1% to about 5% of ammonia saturatedmethanol in CH₂ Cl₂) to give 1.77 (60% yield) of compound 31. ##STR113##

To a solution of 1.54 g of 31 in 8 mL of anhydrous THF was added 11.34mL of lithium aluminum hydride solution (1.0M in diethyl ether) slowly.The resulting solution was stirred at room temperature for 2 hours, and110 mL of diethyl ether was added. Saturated aqueous Na₂ SO₄ solutionwas carefully added to the above mixture till hydrogen evolution ceased.The organic fraction was separated, and the aqueous solution wasbasified with K₂ CO₃ and extracted with ethyl acetate many times. Thecombined organic solutions were washed with brine, dried over anhydrousK₂ CO₃, and then concentrated to give a crude product. The crude productwas purified by flash chromatography on SiO₂ (5% CH₃ OH(NH₃) in CH₂ Cl₂)to give 1.273 g (85% yield) of compound 32. ##STR114##

A solution of 1.2 g of 32 in 100 mL of 0.5N aqueous hydrochloric acidwas heated in a 90° C. oil bath for 30 minutes. After the solution wascooled to room temperature, the mixture was extracted with diethyl ether(4×50 mL). The aqueous solution was concentrated under vacuum to yieldcrude product which was then recrystallized from 2-propanol/diethylether to give 0.5 g (85%) of compound 33; MS (FAB) 166(M+1).

EXAMPLE 6 ##STR115## To a solution of 1.194 g of compound of formula 34and 2.49 mL of tetramethyethylenediamine in 7.5 ml of anhydrous diethylether was added 6.06 ml of 1.3N sec-butyllithium at -78° C. Theresulting solution was stirred for 3 hours 45 minutes at -78° C., and asolution of 1.9074 g of chloromethyl (N-trityl)imidazole 35 in 4 ml oftetrahydrofuran was added dropwise over 15 minutes. After 15 minutes ofstirring at -78° C., the reaction mixture was slowly warmed to roomtemperature for over 1 hour. Saturated aqueous NH₄ Cl solution wasadded. The mixture was extracted with ethyl acetate. The organic layerwas separated, washed with brine, dried over anhydrous sodium sulfateand then concentrated. The residue was purified by flash chromatographyon SiO₂ to give 0.23 g (17%) of product 36. ##STR116##

A solution of 0.23 g of 36 in 20 mL of 0.5N HCl was heated to reflux for45 minutes. After cooling to room temperature, the mixture was extractedwith diethyl ether three times. The aqueous solution was thenconcentrated and the crude product was crystallized with CH₃ OH/diethylether to give 0.75 g (70% yield) of the product 37; MS (CI)152 (M+1).

EXAMPLE 7 ##STR117##

To a solution of 11.59 g of imidazole acetic acid hydrochloride 38 in100 mL of anhydrous methane was added 1 mL of concentrated HCl. Theresulting mixture was refluxed for 5.5 hours, and then cooled to roomtemperature. After concentration of the solvent, 11.9 g (95%) of theproduct 39 was isolated. ##STR118##

To a solution of 7.8 g of 39 in 70 mL of anhydrous DMF at 0° C. wasadded 12.94 g of trityl chloride ((φ)₃ Cl) and 18.4 mL of triethylamine. The resulting solution was stirred at room temperature for 24hours, and the solvent was removed under vacuum. The residue waspurified by flash chromatography on SiO₂ (eluting solvent: CH₂ Cl₂ andincrease polarity slowly by addition of ethyl acetate) to give 16.1 g ofproduct 40 (95% yield). ##STR119##

To a solution of 8.15 mL of compound 41 in 50 mL of anhydrous THF wasadded 26.25 mL of 1.4M methyllithium at -78° C. The above solution wasstirred for 1 hour at -78° C. and a solution of 40A (prepared by theaddition of 25 mL of 1M LiN(Si(CH₃)₃)₂ to a solution of 9.55 g of 40 in100 mL of anhydrous THF at -78° C. and stirring the solution for 2 hoursat -78° C. before transferring) was added by cannula over 30 minutes.Ten minutes later, 4.6 mL of BF₃.(C₂ H₅)₂ O was added to the abovemixture, and the resulting solution was stirred at -78° C. for 2 hours.The reaction mixture was slowly warmed up to room temperature (over 2hours 45 minutes), and then saturated aqueous naHCO₃ solution was added.The organic layer was separated and the aqueous layer was extracted withEtOAc. The organic layer and EtOAc extracts were combined and thecombined organic solution was washed with brine, dried over MgSO₄ andthen concentrated. The residue was purified by flash chromatography(silica gel was deactivated with triethylamine, eluting solvent: 1 to10% of CH₃ OH in EtOAc) to give compound 43 (6.4 g; 60% yield).##STR120##

To a solution of 6.4 g of 43 in 250 mL of anhydrous methylene chloridewas added 11.3 mL of 2.0M trimethyl aluminum. The resulting mixture wasstirred at room temperature for 45 minutes, heated to reflux (5 hours),cooled to 0° C., and to this mixture was added saturated aqueous NaHCO₃solution. The organic layer was separated, washed with brine, dried overNa₂ SO₄ and concentrated. The residue was purified by flashchromatography (silica gel deactivated with triethylamine; elutingsolvent EtOAc to 1 to about 2% CH₃ OH in EtOAc) to give 0.91 g of 44a(trans isomer) and 0.39 g of 44b (cis isomer). ##STR121##

To a solution of 0.3225 g of 44a in 8 mL of anhydrous THF was added 3.28mL of 1M solution of diisobutylaluminium hydride in toluene dropwise atroom temperature. After the addition was complete, the solution wasrefluxed for 2 hours and cooled to room temperature. Water (2 mL) wasadded slowly to the above solution and 20 ml of methylene chloride wasadded to the resulting mixture. The mixture was vigorously stirred untila white solid precipitated out. Filtration and concentration gave crudeproduct, which was purified by preparative TLC (deactivated withtriethylamine; eluting solvent 7.5% CH₃ OH in CH₂ Cl₂) to give 0.187 g(60% yield) of 45. ##STR122##

A solution of 0.148 g of 45 in 12 mL of 0.5N HCl was heated in an oilbath at 90° C. for 0.5 hours. The solution was then cooled to roomtemperature. The mixture was extracted with diethyl ether three times,and the aqueous solution was concentrated to give a crude product. Thecrude product was recrystallized in CH₃ OH/diethyl ether to give 70 mg(85%) of 46; MS(CI) 138 (M+1).

By following the procedures set forth in Example 7, Steps E and F,compound 44b can be converted to the cis isomer of 46.

EXAMPLE 8 ##STR123##

A mixture of 9.78 g of 4-(N-tritylimidazoyl)carboxaldehyde and 9.55 g ofWittig reagent 47 in 30 mL of anhydrous THF was refluxed for 21 hours.An additional 4.8 g of Wittig reagent 47 and 10 mL of THF were added tothe above mixture; the resulting mixture was continually refluxed for 30hours. The solvent was concentrated. The residue was dissolved in CH₂Cl₂ and washed with water. The organic layer was separated andconcentrated. The residue was purified by flash chromatography on SiO₂(CH₂ Cl₂ /EtOAc) to give 6.14 g (81% yield) of 48. ##STR124##

To a mixture of 4.5 g of ketone 48 in 18 mL of CH₃ CN was added 6.62 mLof nitromethane and 75 mL of THF. To the above homogenous solution wasadded 1.835 mL of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) and theresulting solution was stirred at room temperature overnight (18 hours).The reaction mixture was poured into ice cold 01N HCl solution and themixture was extracted with EtOAc. The combined EtOAc extracts werewashed with brine, dried over MgSO₄ and concentrated to give 4.54 g(87%) of product 49. ##STR125##

Compound 49 was reduced by mixing 1.5 g of 49, 1.5 g of Raney-Ni and 1.5g of anhydrous Na₂ SO₄ in 50 mL of absolute ethanol and subjecting theresulting mixture to 60 psi. of H₂ for 26 hours. The reaction mixturewas filtered through a pad of celite and the pad was washed with ethanoland CH₂ Cl₂. The filtrate was concentrated to yield 0.83 g of 50 (62%).##STR126##

A solution of 0.83 g of 50 in 30 mL of 0.5N HCl was heated to reflux for45 minutes. After the mixture was cooled to room temperature, it wasextracted with diethyl ether. The aqueous layer was evaporated todryness to give 0.43 g of crude product 51. ##STR127##

To a mixture of 0.34 g of 51 in 5 mL of anhydrous DMF was added 1.69 mLof triethylamine; the mixture was stirred for 5 minutes and 0.77 mL ofdi-tert-butyldicarbonate ((tBOC)₂ O)was added. The reaction mixture wasstirred for 18 hours at room temperature, filtered and concentrated. Theresidue was dissolved in water and extracted with EtOAc. The combinedorganic extracts were washed with brine, dried over anhydrous Na₂ SO₄and concentrated. The residue was purified by preparative TLC (1:1EtOAc/hexane) to give 0.13 g (24% yield) of 52; MS (M/e) 352 (M+1).##STR128##

A solution of 0.13 g of 52 in 6 mL of EtOAc (saturated with HCl) wasstirred for 45 minutes at 0° C., then the solvent was evaporated undervacuum. The residue was recrystallized in 2-propanol/diethyl ether togive 0.067 (81% yield) of 53; MS(SI) 152(M+1).

EXAMPLE 9 ##STR129## To a solution of lactam 54 (10 mmole; 4.07 g)(synthesized in a manner similar to 5t) in dry THF (55 mL) at -78° C.was added a solution of LDA (11 mmol, 1.18 g) in THF (15 mL). After 45minutes at this temperature, the reaction was warmed to room temperaturefor 20 minutes and then recooled to -78° C. A solution of (tBOC)₂ O (11mmol, 2.41 g) in THF (15 mL) was added and the reaction was slowlywarmed to room temperature. The reaction was then quenched with waterand extracted into diethyl ether. The combined ether extracts werewashed with brine and dried (MgSO₄). Concentration yielded a solid thatwas recrystallized from hexane: 2-propanol. Compound 55, 3.5 g (69%),was obtained as an off-white solid. ##STR130##

To a solution of 55 (6.9 mmol, 3.5 g) in dry THF (50 mL) at -78° C. wasadded a solution of KN(Si(CH₃)₃)₂ (8.63 mmol, 1.72 g) in THF (20 mL)over 10 minutes. An additional 10 mL THF was used to rinse the flask andsyringe. After one hour at -78° C., neat CH₃ I (8.63 mmol, 1.22 g,filtered through basic alumina) was added, and the reaction was warmedto room temperature. After 2.5 hours, the reaction was recooled to -78°C., quenched and saturated NH₄ Cl (pH=7.3) and extracted into diethylether. The combined ether extracts were washed with brine and dried(MgSO₄). Concentration and purification via flash column chromatography(400 g SiO₂ ; 90:10 hexane: 2-propanol) yielded 56 (2.35 g; 65%).##STR131##

To a solution of 56 (4.2 mmol, 2.19 g) in dry CHCl₃ (40 mL) at roomtemperature was added iodotrimethylsilane (10.51 mmol, 2.1 g). After onehour at 40° C., the reaction was diluted with methanol and concentratedon the rotary evaporator. Purification via flash chromatography (150 g,SiO₂, 80:10:10 CH₂ Cl₂ :2-propanol: methanol/ammonia) gave 600 mg (80%)of 57. ##STR132##

Compound 57 (3.6 mmol, 640 mg) was combined with trityl chloride (3.9mmol, 1.48 g) and triethylamine (3.9 mmol, 0.39 g) in dry CH₂ Cl₂ (25mL) at room temperature under nitrogen. After 6 hours, the reaction wasquenched with water and extracted with EtOAc/CH₂ Cl₂ (4:1)(EtOAcrepresents ethyl acetate). The combined organic layers were washed withsaturated aqueous sodium metabisulfite and dried (MgSO₄). The crudematerial was purified on a flash column (175 g SiO₂, 95:5 CH₂ Cl₂ :methanol/ammonia) and yielded 900 mg (59%) of 58. ##STR133##

To a solution of 58 (2.14 mmol, 900 mg) in dry THF (30 mL) was added asolution of LAH in diethyl ether (5.34 mL of a 1M solution). Thereaction was heated to reflux for 2 hours, cooled to room temperature,diluted with diethyl ether, and quenched with saturated aqueous Na₂ SO₃.Solid Na₂ SO₄ was added and the mixture was filtered. The filter cakewas washed with 150 mL of boiling THF. Removal of the solvent on therotary evaporator yielded 920 mg of a crude solid.

To a solution of the crude solid (920 mg) from the previous reaction inTHF (15 mL) was added (t-BOC)₂ O (2.7 mmol, 0.59 g). After 30 minutes,the reaction was diluted with CH₂ Cl₂, washed with water, and dried(MgSO₄). Concentration yielded a crude solid which was purified on aflash column (200 g SiO₂, 80:20 hexane:acetone). This material wasfurther purified via HPLC (SiO₂, 97:3 hexane:2-propanol) to give 230 mg(21%) of 59. ##STR134##

Compound 59 (0.47 mmol, 230 mg) was combined with 15 mL 1N HCl andheated to 90° C. for one hour. The reaction was cooled, filtered, andextracted with diethyl ether. The aqueous layer was concentrated invacuo to give 60 (110 mg, 100%). MS(CI) 166 (M+1).

The following are examples of pharmaceutical dosage forms which containa compound of the invention. As used therein, the term "active compound"is used to designate the compound ##STR135## The scope of the inventionin its pharmaceutical composition aspect is not to be limited by theexamples provided, since any other compound of structural formula I canbe substituted into the pharmaceutical composition examples.

Pharmaceutical Dosage Form Examples EXAMPLE A

    ______________________________________                                        Tablets                                                                       No.   Ingredients       mg/tablet mg/tablet                                   ______________________________________                                        1.    Active compound   100       500                                         2.    Lactose USP       122       113                                         3.    Corn Starch, Food Grade,                                                                         30        40                                               as a 10% paste in                                                             Puritied Water                                                          4.    Corn Starch, Food Grade                                                                          45        40                                         5.    Magnesium Stearate                                                                               3         7                                                Total             300       700                                         ______________________________________                                    

Method of Manufacture

Mix Items Nos. 1 and 2 in a suitable mixer for 10-15 minutes. Granulatethe mixture with Item No. 3. Mill the damp granules through a coarsescreen (e.g., 1/4"0.63 cm) if necessary. Dry the damp granules. Screenthe dried granules if necessary and mix with item No. 4 and mix for10-15 minutes. Add Item No. 5 and mix for 1-3 minutes. Compress themixture to appropriate size and weigh on a suitable tablet machine.

    ______________________________________                                        Capsules                                                                      No.   Ingredient        mg/capsule                                                                              mg/capsule                                  ______________________________________                                        1.    Active compound   100       500                                         2.    Lactose USP       106       123                                         3.    Corn Starch, Food Grade                                                                          40        70                                         4.    Magnesium Stearate NF                                                                            4         7                                                Total             250       700                                         ______________________________________                                    

Method of Manufacture

Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 minutes. AddItem No. 4 and mix for 1-3 minutes. Fill the mixture into suitabletwo-piece hard gelatin capsules on a suitable encapsulating machine.

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand variations thereof will be apparent to those of ordinary skill inthe art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

What is claimed is:
 1. A compound of the formula: ##STR136## or apharmaceutically acceptable salt or solvate thereof, wherein: (A) m isan integer selected from the group consisting of: 0, 1, and 2;(B) n andp are integers and are each independently selected from the groupconsisting of: 0, 1, 2, and 3 such that the sum of n and p is 2 or 3such that when the sum of n and p is 2, T is a 4-membered ring and whenthe sum of n and p is 3, T is a 5-membered ring; (C) each R¹, R², R³,R⁴, R⁶, R⁷, and R⁸ is independently selected from the group consistingof:(1) H; (2) C₁ to C₆ alkyl; (3) C₃ to C₆ cycloalkyl; and (4)--(CH₂)_(q) --R⁹ wherein q is an integer of: 1 to 7, and R⁹ is selectedfrom the group consisting of: phenyl, substituted phenyl, --OR¹⁰,--C(O)OR¹⁰, --C(O)R¹⁰, --OC(O)R¹⁰, --C(O)NR¹⁰ R¹¹, CN and --SR¹⁰ whereinR¹⁰ and R¹¹ are as defined below, and wherein the substituents on saidsubstituted phenyl are each independently selected from the groupconsisting of: --OH, --O--(C₁ to C₆)alkyl, halogen, C₁ to C₆ alkyl,--CF₃, --CN, and --NO₂, and wherein said substituted phenyl containsfrom 1 to 3 substituents; (D) R⁵ is selected from the group consistingof:(1) H; (2) C₁ to C₂₀ alkyl; (3) C₃ to C₆ cycloalkyl; (4)--C(O)OR^(10') ; wherein R^(10') is the same as R¹⁰ defined below exceptthat R^(10') is not H; (5) --C(O)R¹⁰ ; (6) --C(O)NR¹⁰ R¹¹ ; (7) allyl;(8) propargyl; and (9) --(CH₂)_(q) --R⁹, wherein q and R⁹ are as definedabove with the proviso that when q is 1 then R⁹ is not --OH or --SH; (E)R¹⁰ and R¹¹ are each independently selected from the group consistingof: H, C₁ to C₆ alkyl, and C₃ to C₆ cycloalkyl; and, for the substituent--C(O)NR¹⁰ R¹¹, R¹⁰ and R¹¹, together with the nitrogen to which theyare bound, can form a ring having 5, 6, or 7 atoms; (F) the dotted line( . . . ) represents a double bond that is optionally present when m is1, and T is a 5-membered ring, and n is not 0, and p is not 0, and whensaid double bond is present then R² and R⁸ are absent; (G) when m is 2,each R¹ is the same or different substituent for each m, and each R² isthe same or different substituent for each m; (H) when n is 2 or 3, eachR³ is the same or different substituent for each n, and each R⁴ is thesame or different substituent for each n; and (I) when p is 2 or 3, eachR⁶ is the same or different substituent for each p, and each R⁷ is thesame or different substituent for each p.
 2. The compound of claim 1wherein said compound is selected from the group consisting of compoundshaving the formula: ##STR137## wherein R¹, R², R³, R⁴, and R⁸ are asdefined for Formula I.
 3. The compound of claim 1 wherein said compoundis selected from the group consisting of compounds having the formula:##STR138## wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as defined forFormula I.
 4. The compound of claim 1 wherein m is 0 or
 1. 5. Thecompound of claim 4 wherein R⁵ is selected from the group consisting ofH, C₁ to C₂₀ alkyl and (CH₂)_(q) --R⁹ wherein R⁹ is phenyl.
 6. Thecompound of claim 5 wherein R¹ to R⁴ and R⁶ to R⁸ are each independentlyselected from the group consisting of H, C₁ to C₆ alkyl, and --(CH₂ _(q)--R⁹ wherein R⁹ is phenyl.
 7. The compound of claim 6 wherein each R¹ toR⁴ and R⁶ to R⁸ are independently selected from the group consisting ofH, methyl, ethyl, pentyl, benzyl, and 2-phenylethyl.
 8. The compound ofclaim 7 wherein R⁵ is H or methyl.
 9. The compound of claim 1 having theformula selected from the group consisting of: ##STR139## wherein R⁷ isselected from the group consisting of H, C₁ to C₆ alkyl, and --(CH₂)_(q)--R⁹ wherein R⁹ is phenyl.
 10. The compound of claim 9 wherein R⁷ is C₁to C₆ alkyl, R¹ is H, and R² is H.
 11. The compound of claim 1 havingthe formula selected from the group consisting of: ##STR140## whereinR¹, R³ and R⁶ are each independently selected from the group consistingof H, C₁ to C₆ alkyl and --(CH₂)_(q) --R⁹ wherein R⁹ is phenyl.
 12. Thecompound of claim 11 wherein R⁵ is selected from the group consisting ofH and methyl.
 13. The compound of claim 12 wherein R¹ is H.
 14. Thecompound of claim 1 wherein said compound is selected from the groupconsisting of: ##STR141##
 15. The compound of claim 14 having theformula: ##STR142##
 16. The compound of claim 14 having the formula:##STR143##
 17. The compound of claim 14 having the formula: ##STR144##18. The compound of claim 14 having the formula: ##STR145##
 19. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and an effective amount of a Compound of claim 1.